To the Editor – Inositol-requiring enzyme 1 (IRE1) is a central regulator of the unfolded protein response (UPR), and inhibiting its activity is likely to be of benefit for treating diseases related to proteostasis. Hetz et al. recently published a Review Article in Nature Chemical Biology exploring pharmacological targeting of the UPR for disease intervention1 in which they discussed the efficacy of the IRE1 inhibitor B-I09 to induce leukemic regression without causing systemic toxicity in mouse models. They also pointed out a caveat that high concentrations of B-I09 were administered frequently using 100% DMSO as a carrier and suggested that this reduces the translational potential of B-I09. Representing the team leading to the development and optimization of B-109 for clinical use, we believe that some of the features of the compound and the characterization of its translational potential require clarification. B-I09 was developed as a prodrug to target the RNase activity of IRE1, leading to the suppressed expression of XBP1s2. We have used chemical synthesis to tune prodrug stability within a series of B-I09 analogs and achieve spatiotemporal control of inhibitory activity3. Studies using B-I09 have been instrumental in validating the IRE1–XBP1 pathway as a therapeutic target in diseases. For instance, pharmacological inhibition of XBP1s using B-I09 phenocopies genetic deletion of XBP1s in mouse models of chronic lymphocytic leukemia, Burkitt’s lymphoma and chronic graft-versus-host disease (cGVHD)2,4,5. As demonstrated in ERAI reporter mice, B-I09 effectively blocks the RNase activity of IRE1 in dendritic cells6. To the best of our knowledge, B-I09 is the only IRE1–XBP1 inhibitor for which published pharmacokinetic data have guided dosing in mice2. The translational potential of B-I09 is highlighted by consistent results in suppression of XBP1s in targeted cells and amelioration of diseased conditions in various preclinical mouse models2,4,5,7,8. Notably, B-I09 appears to impose no systemic toxicity in treated mice, as documented in several preclinical studies2,4,5,7,8. Relative to other known inhibitors of IRE1, B-I09 has demonstrated remarkable efficacy in multiple preclinical animal models and is well tolerated in vivo. For these reasons, we believe that B-I09 has outstanding potential for translational application. ❐